|Publication number||US7280261 B2|
|Application number||US 11/017,440|
|Publication date||Oct 9, 2007|
|Filing date||Dec 20, 2004|
|Priority date||Dec 20, 2004|
|Also published as||DE602005021301D1, EP1672355A2, EP1672355A3, EP1672355B1, US20060132878|
|Publication number||017440, 11017440, US 7280261 B2, US 7280261B2, US-B2-7280261, US7280261 B2, US7280261B2|
|Inventors||Douglas N. Curry, Richard H. Bruce, Robert T. Krivacic|
|Original Assignee||Palo Alto Research Center Incorporated|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (33), Non-Patent Citations (12), Referenced by (4), Classifications (8), Legal Events (6)|
|External Links: USPTO, USPTO Assignment, Espacenet|
The following co-pending applications, U.S. Ser. No. 10/271,347, filed Oct. 15, 2002, and U.S. Ser. No. 10/616,366 filed Jul. 9, 2003, are hereby both incorporated herein in their entirety.
The present exemplary embodiments relate to the imaging arts, and find particular application in conjunction with low and high-density cell detection, locating, and identifying in blood smears, biological assays, and the like across distinct imaging systems, and will be described with particular reference thereto. However, it is to be appreciated the exemplary embodiments will also find application in imaging, locating and identifying other types of low or high-density features on various substantially planar surfaces and samples, such as imaging semiconductor wafers, imaging particulate contaminants in fluids or thin solid films, and so forth, with such imaging finding specific uses in the printing arts, electronic arts, medical arts, and other scientific and engineering areas.
In rare cell studies, a particular problem arises due to the typically low concentration of the rare cells in the blood or other body fluid. In a typical rare cell study, blood is processed to remove cells that that are not needed. Then a fluorescent material is applied that attaches to antibodies, which in turn selectively attach to a cell surface or cellular protein of the rare cells. The cellular proteins may be membrane proteins or proteins within a cell, such as cytoplasm proteins. The antibodies may also attach to other types of molecules of the rare cell, as well as to DNA.
The fluorescent material may be a fluorescent marker dye or any other suitable material which will identify the cells of interest. A smear treated in this manner, which may include the blood and/or components of the blood, is prepared and optically analyzed to identify rare cells of the targeted type. For statistical accuracy it is important to obtain as large a number of cells as required for a particular process, in some studies at least ten rare cells should be identified, requiring a sampling of at least ten million cells, for a one in one-million rare cell concentration. Such a blood smear typically occupies an area of about 100 cm2. It is to be understood, however, that this is simply one example and other numbers of cells may be required for statistical accuracy for a particular test or study. Other cell identifiers which are being used and investigated are quantum dots and nano-particle probes. Also, while a rare cell is mentioned as a one-in-one-million cell concentration, this is not intended to be limiting and is only given as an example of the rarity of the cells being sought. The concepts discussed herein are to be understood to be useful in higher or lower levels of cell concentration.
In this regard, the ability to scan large numbers of cells at a high rate is considered a key aspect which increases the throughput of testing processes. Therefore, it is considered valuable to provide a system which improves the speed, reliability and processing costs which may be achieved by cell detection systems and/or processes.
Several-aspects may be considered as useful in increasing the throughput and reliability of scans at high rates of speed. For example, it would be useful to have a scanning system which permits high-speed scans in an accurate reliable manner, and a manner for increasing the accuracy with which cell detection occurs which includes decreasing a number of false or ghost images which may exist. While at the same time, maintaining or increasing the amount of data collected during a scan.
In accordance with one aspect of the exemplary embodiments, an imager for imaging sample is disclosed. An imager stage has a planar surface that supports a sample. A light path has a first end arranged to define an input aperture. The input aperture provides for viewing the sample on the imager stage. A distal end is arranged to define an output aperture that is disposed away from the imager stage. A scanning radiation source is arranged to scan a radiation beam along a path that is perpendicular to the sample of the imager stage and proximate to the fiber light path. The scanning radiation source provides a substantially circular spot of illumination on the imager stage sample. The sample provides a light signal that is received by the input aperture and transmitted to the output aperture. A photodetector is arranged to detect the light signal at the distal end, and a processor processes the detected light signals.
In accordance with another exemplary embodiment, an image for imaging a generally planar surface is disclosed. A linearly translating stage linearly translates the surface in at least a first direction. A light path having a first end is arranged to define an input aperture for viewing the sample on the linearly translating stage. A distal end is arranged to define an output aperture that is disposed away from the imager stage. A polygon driven scanner is arranged to scan a beam along a path that is closely proximate the light path so that the beam interacts with the surface to produce a light signal. The light signal is collected by the input aperture and communicated to the output aperture. A photodetector is arranged to detect the light signal at the distal bundle end, and a processor processes the detected light signals.
In accordance with yet another exemplary embodiment, a method for imaging a sample is disclosed. A radiation beam is supplied perpendicular to the sample to be imaged. The perpendicular direction of the radiation beam is maintained as it sweeps along a scan path on the sample. At least some light produced by beam interaction with the sample is reflected in a direction orthogonally away from the sample. Collected light is detected at a selected output region. The sweeping, moving and detecting are coordinated to generate an array of picture elements representative of at least a portion of the sample.
The embodiments may take form in various components and arrangements of components, and in various steps and arrangements of steps. The drawings are only for purposes of illustrating the embodiments.
With reference to
As is known in the art, for cell studies the sample 12 is suitably prepared by drawing a sample of a biological fluid such as, but not limited to, blood or parts of blood from a subject. The fluid sample is treated with a fluorescent material, such as but not limited to a marker dye, that selectively bonds to a cell surface, cellular protein, or other element of the cell, optionally via an anti-body or other intermediary element. Suitable materials are known in the art for marking a number of different cell types of clinical interest, including selected cancer cell types, fetal cells, or other appropriate cells to be considered. The material preferably emits a characteristic luminescence, such as a fluorescence or a phosphorescence, responsive to a selected excitation irradiation, such as irradiation by a selected wavelength or spectrum of light, x-ray irradiation, electron-beam irradiation, or the like. The characteristic luminescence typically has a characteristic wavelength or spectral range of wavelengths.
The treated biological fluid is smeared onto a transparent slide using known techniques. In one suitable technique, a drop of the fluid is applied to the transparent slide 16, and an edge of a second transparent slide or other well-defined, clean edge is used to spread the drop across the slide 16. In another suitable technique, the fluid is applied while the slide 16 is being rotated by a spinner, so that centrifugal forces cause the fluid to smear out substantially uniformly over the slide 16. Other methods for preparing the biological smear can be substituted for the exemplary techniques.
The smear size will depend on the implementation, however, as an example, in one situation for a rare cell concentration of about one rare cell of interest per one million cells in the biological fluid, the smear 14 might contain at least ten million cells and occupy an area of about 100 cm2. Of course, larger or smaller smears can be prepared which are suitable for the anticipated concentration of cells in the sample and the desired minimum measurable cell concentration.
The sample 12 is mounted on an imager translation stage 20 (shown in part) which includes a linearly translatable track 22 that supports the sample 12. A motor 24 connects with the track 22 via gearing 26 to translate the track 22 and the supported sample 12 along a y-direction (indicated by arrows 28). Although translation stage 20 driven by a rotary motor 24 is shown in
With continuing reference to
The optical fiber bundle 40 “morphs” or changes cross-sectional dimensions and shape between the first end 42 to the second end 44 such that the second end 44 includes a plurality of second fiber ends 50 (best seen schematically in
It is particularly pointed out that the spatial relationship between the first fiber ends 46 and the second fiber ends 50 is generally arbitrary. For example, in
To obtain good light transmission, the fiber optic bundle 40 preferably has a high fiber packing factor, for example, fiber optic bundle 40 has a packing factor of about 0.80 or higher. Other factors influencing the light transmission include the polishing or light transmission properties of the tips of the first and second fiber ends 46, 50, the absorption per unit length of the fibers 56, 58, and the overall length of the fibers 56, 58. Fiber bending losses are preferably reduced by avoiding sharp bends of the fiber optic bundle 40. For example, as seen in
With continuing reference to
For cell studies, the excitation radiation 64 preferably produces a spot size on the biological smear 14 which substantially comports with a size of the cells, which may vary in size but are typically about one to thirty microns in size. To obtain such narrow beam focusing, the focusing lens 70 is typically included.
Electronic control unit 80 communicates with laser scanner 66 and the translation microscope stage 20 to raster the radiation beam 64 across the sample. Electronic control unit 80 identifies a beam sweep position as a first coordinate in the x-direction, and a position of the translation microscope stage 20 as a second orthogonal coordinate in the y-direction, to spatially map out the collected characteristic luminescence intensity as a function of position on sample 12. The x- and y-coordinates can be inferred from the laser scan velocity and stage translation velocities. The electronic control unit formats signal and spatial coordinates and displays an image representation on display 100 or the like.
With reference still on
With attention focused now on
With reference to
The laser scanner 110 represented on
The polygon laser scanner 110 of the present embodiment includes a plurality of reflecting mirrors 110 a. The mirrors are actuated by an associated motor 110 b. The motor permits for a linear increase and decrease in speed for smooth control of the movement of mirrors 110 a. A flywheel 110 c associated with the polygon scanner assists in maintaining speed uniformity of the scanner. Scanner arrangement 110, therefore, permits an increase and decrease in speed without an associated jitter which might otherwise occur in a scanning system employing an galvanometer. Particularly, in a galvanometer, the scanning mirror will move back and forth as opposed to the rotational action of the polygon system. This back and forth motion, requires an overcoming of inertia which may result in signal jitter. However, through the use of the mirror arrangement 110 a, motor 110 b, and flywheel 110 c, jitter is substantially if not entirely eliminated from the system.
As will be further noted in
In another embodiment to
Separate output apertures 128, 130 can be separately filtered to view different frequencies of light. Thus, in the embodiments where the fiber optic bundles will have separate output apertures, the data collection scheme in FIG. 5 would be generally duplicated. Particularly two suitable signal detectors 90′ would be arranged to detect each separate collected characteristic luminescent emanating from the output apertures 128 and 130. Two lens arrangements such as 92′ collimate the individual light for each fiber, and separate light blocking filter arrangements 94′ individually (and optionally) remove scattered laser light from the collected light. Thereafter, two second lens arrangements 96′ focus the collimated light onto two separate photodetector arrangements 98′.
A fiber head 134 is disclosed in
Turning now to
Alternatively, in other situations, a benefit will exist to undertake further investigation as part of the imaging systems of
The present application suggests using a single laser for scanning images. It is foreseeable that additional lasers can be used because the use of separate bundles eases the addition of more filters. For example, two filters can be associated with each bundle. It is foreseeable that higher resolution will produce images with improved shape information and will enable better filtering of cells from artifacts. The number of objects that require subsequent microscopic scanning will be reduced accordingly.
The foregoing has been described with reference to exemplary embodiments. Obviously, modifications and alterations will occur to others upon reading and understanding the preceding detailed description. Accordingly, the appended claims as filed and as they may be amended are intended to embrace all such alternative, modifications, variations, improvements and substantial equivalents.
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|Cooperative Classification||G01N2021/6484, G01N21/6428, G01N2201/1085, G01N21/6456|
|European Classification||G01N21/64P4, G01N21/64H|
|Dec 20, 2004||AS||Assignment|
Owner name: PALO ALTO RESEARCH CENTER INCORPORATED, CALIFORNIA
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|Sep 21, 2015||AS||Assignment|
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